Improved metabolic regulation is associated with retinoblastoma protein gene haploinsufficiency in mice

Abstract

Petrov PD, Ribot J, Palou A, Bonet ML. Improved metabolic regulation is associated with retinoblastoma protein gene haploinsufficiency in mice. Am J Physiol Endocrinol Metab 308: E172-E183, 2015. First published November 18, 2014 doi:10.1152/ajpendo.00308.2014 is involved in the control of energy metabolism, and its inactivation protects mice against high-fat diet-induced diabesity. Here, we tested the hypothesis that partial deficiency in the Rb gene could confer metabolic advantages in front of acute challenges to metabolism and as mice age on a regular diet. Rb haploinsufficient (Rb ϩ/Ϫ ) mice and wild-type (WT) littermates were studied from weaning and characterized at 1.5-2.5 mo of age (young adults) and 6 -7.5 mo of age (mature adults). Whereas no differences in body weight or composition were observed at young age, mature adult Rb ϩ/Ϫ mice were leaner than WT littermates, displaying 36% reduced body fat content. At both ages studied, Rb ϩ/Ϫ mice displayed improved blood lipids, enhanced sensitivity to the blood glucose-lowering effect of insulin and to the anorectic effect of leptin, and a reduced respiratory exchange ratio, indicative of an increased use of fatty acids as a fuel. Insulin sensitivity and oral fat tolerance were better maintained with age in the Rb ϩ/Ϫ than the WT mice. Mature adult Rb ϩ/Ϫ mice displayed gene expression changes consistent with increased fatty acid oxidation in white adipose tissue and skeletal muscle and paramount signs of browning in the inguinal white adipose tissue. In conclusion, Rb haploinsufficiency provides metabolic advantages in front of acute metabolic stressors and ameliorates body fat gain and metabolic impairments that normally accompany transition from young to mature adult age. retinoblastoma; insulin sensitivity; fat tolerance; browning THE CONCEPT THAT CELL CYCLE regulatory proteins modulate metabolism in addition to cell proliferation and survival is strengthened by recent research (14). One important protein in this context is the retinoblastoma protein (pRb), encoded by the Rb gene and best known for its role in the control of the cell's proliferation/differentiation switch (25). pRb is the archetypical member of the retinoblastoma protein family, which also includes p107 and p130. In its active hypophosphorylated form, pRb functions as a cofactor for many transcription factors, including E2Fs and cell differentiation-related factors. Interaction with pRb represses the transactivating activity of E2F1 on genes encoding proteins required for entry into the DNA replication phase of the cell cycle while it stimulates the activity of cell differentiation inducers, including master transcription factors required for the differentiation of skeletal myocytes, osteoblasts, and adipocytes (8, 47).Retinoblastoma protein family members have been shown to be involved in nonredundant complex ways in adipogenic commitment and terminal adipogenesis in different model systems of murine and human origin (9 -11, 34 -36). pRb is unique in this context in that its activit...

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“…Five-micrometer-thick sections were stained with hematoxylin/eosin to assess tissue morphology using a Zeiss Axioskop 2 microscope equipped with an AxioCam ICc3 digital camera (Carl Zeiss, Barcelona, Spain) as described before (Petrov et al 2015).…”